title: MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation.
abstract: To identify genes that affect body mass index (BMI) in American Indians who are predominately of Pima Indian heritage, we previously completed a genome-wide association study in 1120 American Indians. That study also included follow-up genotyping for 9 SNPs in 2133 additional subjects. A comprehensive follow-up study has subsequently been completed where 292 SNPs were genotyped in 3562 subjects, of which 128 SNPs were assessed for replication in 3238 additional subjects. In the combined subjects (n = 6800), BMI associations for two SNPs, rs12882548 and rs11652094, approached genome-wide significance (P = 6.7 × 10(-7) and 8.1 × 10(-7), respectively). Rs12882548 is located in a gene desert on chromosome 14 and rs11652094 maps near MAP2K3. Several SNPs in the MAP2K3 region including rs11652094 were also associated with BMI in Caucasians from the GIANT consortium (P = 10(-2)-10(-5)), and the combined P-values across both American Indians and Caucasian were P = 10(-4)-10(-9). Follow-up sequencing across MAP2K3 identified several paralogous sequence variants indicating that the region may have been duplicated. MAP2K3 expression levels in adipose tissue biopsies were positively correlated with BMI, although it is unclear if this correlation is a cause or effect. In vitro studies with cloned MAP2K3 promoters suggest that MAP2K3 expression may be up-regulated during adipogenesis. Microarray analyses of mouse hypothalamus cells expressing constitutively active MAP2K3 identified several up-regulated genes involved in immune/inflammatory pathways and a gene, Hap1, thought to play a role in appetite regulation. We conclude that MAP2K3 is a reproducible obesity locus that may affect body weight via complex mechanisms involving appetite regulation and hypothalamic inflammation.
authors.affiliation: Diabetes Molecular Genetics Section and Diabetes Epidemiology and Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Phoenix, AZ 85004, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Bian
authors.forename: Michael
authors.initials: M
authors.lastname: Traurig
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.forename: Alejandra
authors.initials: A
authors.lastname: Marinelarena
authors.forename: Sayuko
authors.initials: S
authors.lastname: Kobes
authors.forename: Yunhua L
authors.initials: YL
authors.lastname: Muller
authors.forename: Alka
authors.initials: A
authors.lastname: Malhotra
authors.forename: Ke
authors.initials: K
authors.lastname: Huang
authors.forename: Jessica
authors.initials: J
authors.lastname: Perez
authors.forename: Alex
authors.initials: A
authors.lastname: Gale
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015992:Body Mass Index; D001835:Body Weight; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D007198:Indians, North American / Q000235:genetics; D007249:Inflammation / Q000235:genetics*; D008137:Longitudinal Studies; D048371:MAP Kinase Kinase 3 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human